Autophagy Is a Renoprotective Mechanism During in Vitro Hypoxia and in Vivo Ischemia-Reperfusion Injury
Autophagy Is a Renoprotective Mechanism During in Vitro Hypoxia and in Vivo Ischemia-Reperfusion Injury
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DOI：
10.2353/ajpath.2010.090594
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发表时间：
2010-03-01
影响因子：
6
通讯作者：
Dong, Zheng
中科院分区：
文献类型：
--
作者：
Jiang, Man;Liu, Kebin;Dong, Zheng
自噬调节细胞质成分的大量降解和循环，以维持细胞内环境的稳定。在应激反应中，自噬被诱导，并可能导致细胞死亡或作为一种细胞生存机制。对自噬在肾脏病理生理学中的作用知之甚少。本研究采用体外和体内的肾缺血再灌注模型，研究了自噬及其在肾细胞损伤中的病理作用。我们发现低氧(1%O-2)可诱导培养的肾小管上皮细胞自噬。用3-甲基腺嘌呤或小干扰RNA敲除Beclin-1和ATG5(两个关键的自噬基因)来阻断自噬，使肾小管细胞对低氧诱导的细胞凋亡敏感。在体外缺血再灌注模型中，缺氧(0%O-2)在无糖缓冲液中孵育不能诱导自噬，但在随后的恢复/再灌注期可诱导自噬。在这个模型中，抑制自噬也促进了细胞凋亡。在体内，在小鼠肾缺血再灌流过程中，肾组织发生了自噬。自噬在缺血期不明显，但在再灌注期显著增强。氯喹和3-甲基腺嘌呤抑制自噬加重了肾缺血/再灌注损伤，如肾功能、组织学和肾小管细胞凋亡所示。总而言之，就是结果。在缺氧性和缺血性肾损伤中显示自噬诱导。在这些病理条件下，自噬可能为细胞存活提供了一种保护机制。(Am J Pathol2010,176：1181-1192；DOI：10.2353/ajpath.2010.090594)
Autophagy mediates bulk degradation and recycling of cytoplasmic constituents to maintain cellular homeostasis. In response to stress, autophagy is induced and may either contribute to cell death or serve as a cell survival mechanism. Very little is known about autophagy in renal pathophysiology. This study examined autophagy and its pathological role in renal cell injury using in vitro and in vivo models of ischemia-reperfusion. We found that hypoxia (1% O-2) induced autophagy in cultured renal proximal tubular cells. Blockade of autophagy by 3-methyladenine or small-interfering RNA knockdown of Beclin-1 and ATG5 (two key autophagic genes) sensitized the tubular cells to hypoxia-induced apoptosis. In an in vitro model of ischemia-reperfusion, autophagy was not induced by anoxic (0% O-2) incubation in glucose-free buffer, but was induced during subsequent recovery/reperfusion period. In this model, suppression of autophagy also enhanced apoptosis. In vivo, autophagy was induced in kidney tissues during renal ischemia-reperfusion in mice. Autophagy was not obvious during the ischemia period, but was significantly enhanced during reperfusion. Inhibition of autophagy by chloroquine and 3-methyladenine worsened renal ischemia/reperfusion injury, as indicated by renal function, histology, and tubular apoptosis. Together, the results. demonstrated autophagy induction during hypoxic and ischemic renal injury. Under these pathological conditions, autophagy may provide a protective mechanism for cell survival. (Am J Pathol 2010, 176:1181-1192; DOI: 10.2353/ajpath.2010.090594)